Relevance of the thyroid hormones–αvβ3 pathway in primary myeloma bone marrow cells and to bortezomib action

Abstract

Thyroid hormones (T₃ and T₄) induce proliferation in multiple myeloma (MM) cell lines via the αvβ3 integrin–mitogen-activated protein kinase (MAPK) pathway. We further show in primary MM bone marrow (BM) samples (n = 9) induction of cell viability by 1 nM T₃ (13%, p < 0.002) and more potently by 100 nM T₄ (21–45%, p < 0.0002) and a quick (1 h) and long-lasting (24 h) pERK activation, which was inhibited in the presence of β3 but not β1 blocking antibodies. Involvement of the integrin was further shown by two disintegrins, Arg-Gly-Asp (RGD) and echistatin peptides, which occluded the effects of T₃/T₄ on viability, proliferating cell nuclear antigen (PCNA) (proliferation marker) and apoptotic gene expression. Lastly, T₃/T₄ significantly opposed bortezomib (25 nM) cytotoxicy, as confirmed by several methods. In summary, our results imply that endogenous thyroid hormones in myeloma are factors that may support cell growth, with relevance to bortezomib action.

Keywords::

• αvβ3
• integrin
• myeloma
• thyroid hormone

Acknowledgements

This work was partially supported by the Li Ka Shing Foundation (LKSF). The work of Keren Cohen was done in partial fulfillment of the requirements for a PhD degree from the Sackler Faculty of Medicine, Tel Aviv University, Israel.

Potential conflict of interest:

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Supplementary material available online

Tables showing patient data and primer sets for PCR analysis.